Process for the preparation of optically active 2-aryl-alkanoic acids, especially 2-aryl-propionic acids

ABSTRACT

A chemical process is disclosed for the preparation of a pharmaceutically active compound in an enantiomeric form either (R) or (S) of the structure ##STR1## and a suitable pharmaceutical salt, e.g. alkali or earth metal, D-glucamine or D-ribamine, where R 1  represents an optionally substituted aryl group same as phenyl or naphthyl group, optionally including a heterocyclic ring system, which is optionally substituted, or represents a hetero-aromatic ring system optionally containing in addition to carbon atoms one or more atoms selected from the group consisting of nitrogen and oxygen; the enantiomeric R or S-compounds of (I) are obtained from a suitable ketone (II) by reduction with an LiAlH 4   -  &#34;chiraldid-complex&#34; to the corresponding S- or R-alcohol, following chlorination with retention of configuration, and producing a steriochemical pure R or S magnesium organic compound by subsequent carbonation with carbon dioxide in the presence of a ligand by keeping the stereochemical configuration R or S at 98% enantiomeric excess at least including high yields, and if desired converting compounds (I) into a pharmaceutically acceptable salt or ester thereof. Especially pharmaceutically complexes with D-glucamine and D-ribamine in a stoichiometric ratio of 1:1, including salts comprised of N-cationic detergents with 2-(S)-aryl-alkanoic acids.

This application is a continuation-in-part of our copending applicationSer. No. 352,269, filed May 16, 1989, abandoned.

FIELD OF THE INVENTION

The present invention relates to a stereospecific chemical synthesis ofoptically pure enantiomers of 2-aryl-alkanoic acids, especially those of2-aryl-propionic acids, in high chemical yields and large quantities.Starting from unsymmetrical ketones produced, e.g. by a Friedel-Craftsreaction, the stereospecific reduction to the S- or R-enantiomeric form,respectively, of the corresponding carbinol is achieved by a complexedreducing reagent consisting of lithium-aluminium-hydride and anoptically pure diamino-alcohol, resulting in high chemical yields, wherethe enantiomer (R or S) has a high optical purity. The subsequentchemical steps in the chemical synthesis include halogenation by keepingthe retention of the chiral configuration in an almost quantitativereaction.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a chemical process for preparingoptically active 2-aryl-alkanoic acids especially 2-aryl-propionic acidsin high chemical yields and >98% optical purity, including novelintermediates of excellent optical yield (>97% as determined by rotationand NMR- methods). In particular, this invention concerns a novelchemical process for the preparation of a stereoselective synthesis of achiral alcohol, a chiral magnesium or a mercury organic compoundcomprising two main steps: a stereoselective halogenation of a chiralalcohol, followed by metallation or by a reaction with alkali cyanide,and subsequent conversion by retention of configuration to thecarboxylic acid. This invention especially concerns an overallenantiomeric-selective chemical synthesis since it allows the productionof both enantiomeric forms, R and S separately in high chemical yieldand excellent optical purity, only by changing solvent, temperature oradditions of the "chiraldid" complex, without racemization.

Three different routes can be pursued to obtain optically pure2-aryl-alkanoic acids at high chemical yields:

i) the halides can be metallated with magnesium or mercury andsubsequently treated with carbon dioxide;

ii) or by producing the corresponding nitriles by changing configurationof the chiral carbon atoms (R→S, or S→R) and subsequent hydrolysis tothe 2-aryl-alkanoic acids;

iii) or by treatment of the enantiomeric halides with sodiumtetracarbonyl ferrate-II [Na₂ Fe (CO)₄ ] in the presence of carbonmonoxide (CO); and subsequent treatment with sodium hypochlorite (NaOCl)and acid hydrolysis or by treating with a halogen (e.g. J₂) in thepresence of an alcohol to give the enantiomeric ester, or in thepresence of J₂ and water to yield, respectively, the corresponding freecarboxylic acid.

This chemical process yields high optically pure 2-aryl-alkanoic acids,especially of 2-aryl-propionic acids, at high chemical yields.

BACKGROUND OF THE INVENTION

In 1981, Shen (Shen T. Y., in: Wolff, M. F. (ed) Burger's MedicinalChemistry, 4th edition, part III, Wiley, Interscience, New York, pp.1205-1271) reviewed the medicinal aspects of the aryl-acetic acids andtheir 2-methyl analogues, especially the 2-aryl-propionic acids. Inparticular, it has been reported that the in vitro anti-inflammatoryactivity resides in the S-enantiomer which is an optically activeenantiomer of the racemate (R,S)-2-aryl-propionic acid which is up to150 times as active as its R-enantiomer as described by Adams et al. (S.Adams et al., J. Pharm. Pharmacol., 28, 1976, 256; A. J. Hutt and J.Caldwell, Chemical Pharmacokinetics 9, 1984, 371). Moreover, the chiralinversion by the metabolism in man of 2-aryl-propionic acids of theR-(-) enantiomer to the biologically active S-(+) enantiomer, especiallyin case of ibuprofen (R,S)-2-(4-isobutylphenyl)-propionic acid),supports the pharmacologically active principle of the S-(+)-enantiomerwhich is also supported by the studies of the S-enantiomer of Naproxen(A. J. Hutt and J. Caldwell, J. Pharm. Pharmacol., 35, 1983, 693-694).In addition, there is no metabolic chiral inversion to the correspondingR-(-)-enantiomer of the S-(+) form in man, although some stereochemicalinversion has been observed in rats occasionally, possibly due tounknown stereochemical interations of the (S)-(+) and R-(-) enantiomersat the site of action.

Since the conversion of the R-(-)-2-aryl-propionic acids to thepharmacologically active S-(+)-enantiomer is a reaction of greatmedicinal impact, it is likely that certain benefits will be obtained bythe use of the S-(+)-enantiomers of 2-aryl-alkanoic acids as compoundsas opposed to the racemates. The use of the S-(+) enantiomers wouldpermit reduction of the dose given, reduce the gastro-intestinal sideeffects, reduce the acute toxicity, remove variability in the rate andextent of inversion, and in addition will reduce any toxicity arisingfrom non-specific reactions.

Therefore, there is need of a process capable of operating on anindustrial scale in order to produce economically attractive yields ofthese S-(+) enantiomers of high optical purity >98%, by applying astereospecific chemical method. Optically pure enantiomers of2-aryl-alkanoic acids, especially 2-aryl-propionic-acids which areapproved for pharmaceutical use as a pure, optically activestereoisomer, e.g. S-(+)-(6-methoxy-2-naphthyl)-propionic acid(Naproxen) or S-(+) ibuprofen, can be obtained by using conventionalways of racemic separation by applying optically active bases, e.g.2-phenyl-ethyl-amine, N-methyl-glucamine, cinchonidine, brucine orD-(-)-threo-1-p-nitrophenyl-2-aminopropan-1,3-diol or throughbiochemical racemate separation (P. Cesti and P. Piccardi, Eur. Pat.Appl. EP 195,717; 1986, J. S. Nicholson, and J. G. Tantum, U.S. Pat. No.4,209,638, 1980), or by high performance liquid chromatographictechniques (see G. Blaschke, Angew. Chem. 92, 14-25, 1980). However,these methods of applying optically active bases or enzymes (pig liveresterase) have the drawback common to all these processes of highmaterial costs, manufacturing labor and equipment for the recovery andracemization of the undesired optical stereoisomer not counting theenergy necessary for redistillation of the solvents, low yields ofcrystalline compounds of high optical purity from the mother liquors.Thus the elimination of these resolution steps can result in substantialsavings in material costs, manufacturing, labor and equipment.

Methods for synthesizing racemic 2-aryl-alkanoic acids, especially2-aryl-propionic acids and in particular to R, S-ibuprofen are wellknown, see, for example, Tanonaka, T., et al., DE 3523082 Al, (1986),who uses microorganisms; JP-PSEN 40-7491 (1965); 47-18105, (1972); JP-OS50-4040, (1975); DE 2404159 (1974); DE 1443429 (1968) by J. S. Nicholsonand S. S. Adams; DE 2614306 by Bruzzese, T., et al., (1976); DE 2605650by Gay, A., (1976); DE 2545154 by Heusser, J., (1976); and DE 2404160 byKogure, K., et al., (1974).

Surprisingly, only a few methods for a stereospecific chemical synthesisfor 2-aryl-alkanoic acids, especially 2-aryl-propionic acids, are known.Piccolo et al. (J. Org. Chem. 50, 3945-3946, 1985) describe astereospecific synthesis by the alkylation of benzene or isobutylbenzenewith (S)-methyl-2-[(chlorosulfonyl)-oxy] or 2-(mesyloxy) propionate inthe presence of aluminium chloride yielding(S)-methyl-2-phenyl-propionate in good chemical yield (50-80%) andexcellent optical yield of >97% as determined by rotation throughinversion of configuration at the attacking carbon atoms. The reactionconditions are very similar as described in some patents (Jpn. KokaiTokkyo Koho 5808045; Chem. Abstracts, 1983, 98; 14313 k; Jpn. KokaiTokkyo Koho 7979246; Chem. Abstracts, 1980, 92, 6253 f) where racemicreagents have been used. Extensions of this type of reactions to otheraromatic substrates, e.g. toluene, isobutylbenzene, tetraline, anisole,naphthalene, 2-methoxy-naphthalene are described in Jpn. Kokai TokkyoKoho 7971932; Chem. Abstracts 1979, 91, 20125 b; Jpn. Kokai Tokkyo Koho78128327; Chem. Abstracts 1978, 89, 23975 y; Jpn. Kokai Tokkyo Koho81145241; Chem. Abstracts 1982, 96, 68650 z; Jpn. Kokai Tokkyo Koho78149945; Chem. Abstracts 1979, 90, 168303 h; Jpn. Kokai Tokkyo Koho7844537; Chem. Abstracts 1978, 89, 108693 h; Jpn. Kokai Tokkyo 77131551;Chem. Abstracts 1978, 88, 104920 h. In a recent paper Piccolo et al. (J.Org. Chem 52, 10, 1987) describe a synthesis leading to R-(-) ibuprofen,whereas Tsuchihashi et al. (Eur. Pat. Appl. EP 67,698, (1982); Chem.Abstracts 98, 178945 y, (1983) report a stereospecific synthesis of theR-(-) ibuprofen- methylester with excellent yields of about 75.0% andhigh optical purity (>95%) in contrast to Piccolo et al. (J. Org. Chem.32, 10, 1987) having an optical purity of 15% only for the R-(-)ibuprofen. However, the same authors have reported chemical yields of68% of S-(+) ibuprofen having an optical purity of 75-78%, only.Hayashi, et al. (J. Org. Chem. 48, 2195, 1983; in: Asymmetric Reactionsand Processes In Chemistry; eds E. L. Eliel and S. Otsuka, ACS-SymposiumSer. 1985, 1982, 177) describe a stereospecific synthesis of S-(+)ibuprofen through asymmetric Grignard cross-coupling which are catalyzedby chiral phosphine-nickel and phosphine- palladium complexes. Theenantiomeric excess of the coupling products with various alkenylhalides under the influence of the above-mentioned metal phosphinecomplexes, including amino acids, depends strongly on the ligand andranges up to 94% with enantiomeric excesses in the 60-70% range. A veryuseful ligand has been found in chiral 2-aminoalkyl phosphines achievingreasonable chemical yields and high optical purity. Furthermore,optically active 2-aryl-alkonates have been synthesized via aFriedel-Crafts synthesis by Sato and Murai (Jpn. Kokai Tokkyo Koho JP61,210,049 t 86,210,049, 1986) yielding 46% S-(+) ibuprofen. Giordano etal. (EP application 0 158 913, 1985) has reported a process for thepreparation of optically active 2-aryl-alkanoic acids and intermediatesthereof by halogenation on the aliphatic carbon atom to the ketal groupand rearrangements of the haloketals yielding pharmacologically active2-aryl-alkanoic acids. A stereochemical synthesis of 2-aryl-propionicacids is described by Robertson et al. (EP application 0 205 215 A2,1986) using 2-(R₁)-alkane as the carbon source for the fungi Cordycepsin particular for Cordiceps militaris, yielding enantiomeric S-(+)products of high optical purity.

Methods for the synthesis of anti-inflammatory 2-aryl-propionic acidsare listed in the review by Rieu et al. (J. P. Rieu, A. Boucherle, H.Coussee and G. Mouzin, Tetrahedron Report No. 205, 4095-4131, 1986),also. However, this report is mostly concerned with the racemates ratherthan an evaluation of stereospecific chemical synthesis of 2-aryl-propionic acids.

DETAILED DESCRIPTION OF THE INVENTION

This invention describes the stereospecific synthesis of the S- orR-enantiomers of 2-aryl-alkanoic acids, particularly 2-aryl-propionicacids, which can be applied easily in chemical plants. The advantage ofthis process is the use of simple available and economical chemicals,e.g. ketones, and asymmetric reduction with chiral reagents from lithiumaluminum hydride complexes with (2S, 3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol or 2,2'-dihydroxy-1,1'-binaphthyl [whichcan be re-used after the reaction], thionyl-chloride (bromide),magnesium or cyanide in conjunction with sodium- carbonyl-ferrate (Na₂Fe(CO)₄, Collman's reagent) in order to produce economical yields ofS-(+) or R-(-)-2-aryl-alkanoic acids, preferably S-(+)-ibuprofen andS-(+) naproxen, of high optical purity ( >98%).

The 2-aryl-alkanoic acids prepared according to the present inventionfall within the chemical formula: ##STR2## in which R is lower alkyl, Aris preferably a monocyclic, polycyclic or ortho-condensed polycyclicaromatic group having up to twelve carbons in the aromatic system, e.g.phenyl, diphenyl, and naphthyl. The substituents on these aromatic ringsystems comprise one or more halogen atoms, C₁ -C₄ alkyls benzyl,hydroxy, C₁ -C₂ alkoxy, phenoxy and benzoyl groups. Examples of suchsubstituted aryls are: 4-isobutyl-phenyl, 3-phenoxy-phenyl,2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl, 6-methoxy-2-naphthyl,5-chloro-6-methoxy-2-naphthyl and 5-bromo-6-methoxy-naphthyl,4-chlorophenyl, 4-difluoro-methoxy-phenyl, 6-hydroxy-2-naphthyl, and5-bromo-6-hydroxy-2-naphthyl.

For reasons of clarity we define the meaning of the following terms andexpressions used throughout this invention as follows:

Chiral refers to a chemical structure which has an asymmetric center, atleast. The configuration of the asymmetric carbon atom is classified as"R" or "S" in accordance with the Cahn-Ingold-Prelog rules. Enantiomeror enantiomorph defines a molecule which is non-superimposable on itsrespective mirror image. Enantiomeric excess, "e.e", refers to adefinition which means percentage of the predominant enantiomersubtracted from the other enantiomer.

The ketones of the chemical formula (II) below are well known and areeasily prepared by known methods through Friedel-Crafts acylation if notcommercially available.

The stereospecific reduction to the correspondingS-(+)-1-(4-isobutylphenyl)-hydroxyethane (III) is accomplished byreacting the unsymmetrical ketone (II) with LiAlH₄ in complex with(+)-4-dimethylamino-3-methyl-1,2- diphenyl-2-butanol in etheral (or THF)solutions. Due to different conditions e.g. temperature, adding thereducing reagents, reaction time, by applying this particular reactionone can obtain easily the S-2-(4-isobutylphenyl)-2-hydroxy- ethane orthe corresponding R-enantiomer in good chemical yields (almost 100% inchemical yield) and high optical purity (>95%).

A schematic route for this particular synthesis of the S- orR-enantiomer is shown in FIG. 1 below, whereas FIGS. 2 and 3 show theprocedure for obtaining S-(+) or R(-)-ibuprofen. This route (FIG. 2)stands for a general route to obtain pure enantiomers of2-aryl-propionic acids, useful for industrial processes.

The asymmetric reduction with lithium aluminium hydride (LiAlH₄) incomplex with (+)-(2S, 3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol (S. Yamaguchi and H. S. Mosher, J. Org.Chem. 38, 1870, 1973) of the ketone (II) gives either (R)-(-) or(S)-(+)-1-(4-isobutylphenyl)-hydroxyethane in 98-99% enantiomeric puritydepending upon use of this reagent either immediately after itspreparation or upon aging overnight or refluxing for a few minutes. Thisparticular reversal in stereoselectivity with age of the complexingreagent ("chiraldid reagent") can be used to provide 2-substituted-2-hydroxyethane derivatives having high optical purity andvery good chemical yields of about 95% and more. These chemical yieldswith high optical purity can be obtained particularly from differentcarbonyl substrates of the formula (I'). ##STR3##

The extent of stereoselectivity is determined by NMR methods by treatingthe carbinol obtained with excess acid chloride from(R)-(+)-2-methoxy-2-trifluoromethylphenylacetic acid in pyridine asdescribed by J. A. Dale, D. C. Dull, and H. S. Mosher, J. Org. Chem. 34,2543, (1969). The signals of both the 0-methyl and α-methyl groups ofthe R,R-diastereomer from methylphenylcarbinol appear at higher fieldsthan those of the R, S-diastereomers. The peaks are clearly separated ona T-60 instrument and relative peak heights are shown to give a goodapproximation of the isomeric composition. Further, the ¹⁹ F resonancesfor the 2 --CF₃ group at 94,1 MHz can be used also and readilyintegrated Applying a NMR shift reagent, e.g. Fn(fod)₃ (0, 1M) can beused also to discriminate between the different R, R-diastereomers andR, S-diastereoisomers, respectively, so that quantitative integration ofthe respective 0-methyl signals is readily possible.

Another effective asymmetric reduction of prochiral carbonyl compoundsaccording to the formula (II) with a hydride reagent containing a chiralauxiliary ligand can be achieved by using LiAlH₄ in complex withoptically pure 2,2'-dihydroxy-1,1'-binaphthyl in the presence of ahydroxylic compound R'OH. The enantio-selectivity is virtually complete(FIG. 4 below) in accordance with recent observations by Noyari et al.(R. Noyari, I. Tomino and Y. Tanimoto, J. Amer. Chem. Soc. 101,3129-3130, 1979).

Since both R- and S-forms of the carbinols are readily accessible inoptically pure forms, both methods allow the synthesis of bothenantiomers of these carbinols from carbonyl compounds. Furthermore, thereduction of simple dialkyl ketones does not give satisfactory opticalyields as these unsymmetric substituted ketones of formula II.

With respect to the reaction of LiAlH₄-(+)-4-dimethyl-amino-3-methyl-1,2-diphenyl-2-butanol with the ketones(II), it has been found that the optical yield increases by lowering thereaction temperature when using ether as a solvent. However, by applyingtetrahydrofurane (THF) or 1,2-dimethoxy-ethane the reaction temperatureis not crucial when the reaction conditions are below 30° C. In bothcases the chemical yields are almost 95%.

The synthesis of R-(-) or the S-form from the ketone (II) including thesubsequent transformations to the S- or R-enantiomer of the carboxylicacids, for obtaining high chemical yields, depends on the optical purityof the S- or R-enantiomers of the substituted 1-hydroxyethane. It hasbeen found that the effects of temperature, concentration, solvent,time, ratio of the reactants, and velocity of stirring uponstereoselectivity of this reduction is of importance for obtaining highchemical yields ( >90%) of the optically pure S- or R-enantiomericforms.

Of foremost importance in the observed increase in chemical yield of thecorresponding enantiomers (R or S) having high optical purity accordingto this reduction to the carbinol, is that the stereoselectivity isstrongly dependent upon the length of time that the reagent, e.g. LiAlH₄R*OH (R*OH is (+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol-2-butanol) has beenpermitted to stand before its use for reducing the ketone as asubstrate. Accordingly, stirring velocity and time are important factorsfor producing the R- or S-enantiomeric forms in high chemical yield andoptical purity, whereas the time parameter influences thestereoselectivity if R-(-) or S(-) is being produced from the carbonylsubstrate. The stirring (mixing) in the absence of any oxygen andmoisture determines mainly the chemical yield. According to thisinvention when, for example, 2-(4-isobutylphenyl)-methyl-ketone or1-[4-2-methylpropyl]phenyl-ethanone [CAS Registry #38861-78-8] is addedto the reagent, e.g. LiAlH₄ R*OH, at 4° C., (0° C.-4° C.) either 1minute or 5 minutes after its preparation, an almost quantitative yieldof R-(-)-2-(4-isobutyl-phenyl)-2-hydroxyethane is formed whencontinuously stirred. The preparation of the reducing agent is performedby mixing LiAlH₄ R*OH with the ketone in a molar ratio of 1.0:2.5;normally a pasty cake is obtained in etheral solution at 0°-4° C.However, continuous stirring has to be provided in order to have anactive reducing reagent.

The preparation of the reducing reagent, e.g. LiAlH₄ R*OH, in etherealsolution especially the colloidal state rather than the "caky" orsuspended state influences the optical purity; the almost quantitativereduction of the carbonyl substrate which is governed by stirring themixture of LiAlH₄ R*OH and ketone, the colloidal state of the reducingreagent, LiAlH₄ R*OH, rules the optical purity of the reagent which isnearly 95-98%.

However, when the reducing reagent is permitted to stand for eight hoursor is refluxed in ether without stirring before the same carbonylsubstrate is added, a 95-98% yield of the S-(+)-enantiomeric form of thecarbinol, which is 95% optically pure, is obtained.

The observed reversal in stereoselectivity is associated with thecolloidal state of LiAlH₄ (R*OH)_(n) and the more soluble form of"LiAlH_(4-n) (R*OH)_(n) "+nH₂, still in colloidal state; however, morein a state of microemulsion. Stirring (continuous mixing) for a shortperiod of time (time-scale minutes) is essential according to thereaction scheme:

    LiAlH.sub.4 +nR*OH=LiAlH.sub.n-4 (OR*)+nH.sub.2

which can be measured by the evolution of hydrogen and forming amicroemulsion rather than a precipitate. Practically, the constancy ofthe density of the state of the LiAlH_(4-n) (OR*) or the initial complexLiAlH_(4-n) R*OH in ethereal or THF solutions is a reasonable assumptionfor the stereoselectivity, and any variation which is being applied tothe colloidal system has effects on the chemical yields, rather than theoptical purity. In accordance with this invention the successfulpreparation of the S-enantiomer of the carbinol from the correspondingketone (II) as a substrate is preferred by allowing the reducing agentto stand for eight hours in ethereal or THF solutions at temperaturesbetween -7° C.-0° C. before the corresponding ketone is added. Thereduction is carried out and completed in 10-12 hours at 20° C. undercontinuous mixing.

The R-enantiomer of the carbinol from the corresponding ketone (II) isobtained preferably by forming the complex reducing agent, LiAlH_(4-n)(OR*)_(n) at 0° C. (down to -50° C.) and immediately adding (between5-10 minutes) of the corresponding ketone in ethereal or THF solutions,followed by continuous stirring over a period of time of 8-12 hours at20° C.

It has been found that the stereoselectivity of the reduction to theR-carbinol increases with decreasing temperature (-70° C. to 0° C.) bypreparing the active reducing complex, whereas the stereoselectivity ofthe soluble active reducing reagent for the S-carbinol decreases withtemperature. Reaction temperatures for forming the active reducingspecies, e.g. LiAlH_(4-n) (OR*)_(n), and aging (time of standing ofLiAlH_(4-n) (R*)_(n)) is important to stereoselectivity. However, themain density of the reaction mixture consisting of LiAlH_(4-n) (OR*)_(n)and the ketone with respect to the industrial process should be constantthroughout the series of additions of the ketone. Thus, if thevolumetric feed rate of the ketone with respect to the active reducingreagent is in the steady state, the rate of outflow from the reactionwill be the same as the volumetric feed rate of the reacting ketone. Soin terms of engineering design, it can be treated as a homogenousreaction mixture because there is complete mixing on a molecular scalewith no particular residence time. If the feed consists of a suspensionof colloidal particles, though there is a distribution of residencetimes among the individual particles, the mean residence time doescorrespond to the ratio of volume to volumetric feed rate, if the systemis ideally stirred and mixed.

The reaction kinetics for conversion of the ketone to the correspondingenantiomeric carbinols can be enhanced by carrying out the reaction inthe presence of 3A or 4A molecular sieves (zeolites) during thereaction. The advantages of using these sieves include, as discovered byapplying this mechanism, economy, ease of isolation, increasing chemicalyields including improving optical purities and enantiomeric excess, andthe potential for in situ derivatization of the product. According toour invention with the stereospecific reduction of the ketones to thecorresponding enantiomeric carbinols in the absence of (i) water, comingfrom incompletely dried reagents, solvents, equipment and moisture, (ii)diol ethers, generated by in situ during side reactions in the presenceof water, (iii) hydroperoxides and (iv) improper colloidal state of thereducing chiral complex, are disadvantages in not using the molecularsieves during the reaction, causing decrease in chemical yields ofoptically pure corresponding carbinols.

It has been found that the highest stereoselectivities for both forms ofthe reactive reducing reagent, LiAlH_(4-n) (OR*)_(n) are obtained forratios of LiAlH₄ to R*OH between 1.0:2.3 to 1.0:2.5 in accordance withYamaguchi and Mosher (J. Org. Chem. 38, 1870, 1973), and does not appearto be critical for the processes described here. It has been found thatthe preparation of the active reducing agent, LiAlH_(4-n) (OR*)_(n), inbenzene, toluene, pentane and hexane instead of ether, THF,1,2-dimethoxy-ethane, does not improve stereo- selectivities over morepolar solvents, e.g. ether, etc. However, nonpolar solvents are veryuseful for reducing ketones with the active reducing reagent whenmethoxy- or chloro, bromo, and fluoro substitutents are located in thearyl-groups since they are not affected in these solvents by thereducing reagent, hence high chemical yields with high optical puritiesare obtained. One advantage of using this chiral reducing reagent forpreparing enantiomeric carbinols of high optical purity on a large scalebasis is the recovery of the(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol after reaction withhydrochloric acid and subsequent neutralization with sodium carbonate.So the optically active diamino alcohol can be re-used which makes thisreducing step very economical at low costs, and almost quantitativeyields.

The same procedure can be applied by using 2,3'dihydroxy-1,1'binaphthylas well as for the recovery of this particular reducing agent (FIG. 4below).

Another procedure which brings about the asymmetric reduction ofketones, e.g. II, employs a complex between boron hydride and tetrahydrofuran (BH₃ :THF) and the chiral amino-alcohol,S-(-)-1,1-diphenyl-prolinol according to well-established methodoloy(Corey, Bakshi and Shibata, J. Amer. Chem. Soc. 109, 5551 (1987)). Theyields are 99.7%, with 97% ee (FIG. 5).

Stereospecific halogenation of the enantiomeric carbinol, R or S, (III),by keeping retention of configuration of the chiral carbon can beperformed either with thionylchloride or thionylbromide, or cyanuricchloride in high chemical yields (almost quantitative) and high opticalpurity. Preferably, the halogenation is performed in 1,4- dioxane,water-free, when using high amounts of the carbinols, whereas drypyridine can be used also. The enantiomeric carbinols are normallydissolved in 1,4-dioxane at 20° C. by adding the stoichiometric amountsof thionylchloride dropwise under continuous mixing over a period oftime of one hour. The reaction should continue in the case ofthionylchloride or bromide for 30 minutes further. The excess of SOCl₂or SOBr₂ is eliminated by passing a dry stream of nitrogen through thereaction solution at 20° C. for approximately five hours, unless the R-or S-enantiomeric chloride is being recovered through high vacuumdistillation.

A typical procedure for preparation of the enantiomeric chlorideinvolves heating of the enantiomeric carbinols with powdered cyanuricchloride (1 mol) to 10°-20° C. above the boiling point of the carbinolsor in the presence of a base (0.5 mol NaOCH₃ or NaOBu). After theaddition (ca. 1 -1,5 h), the reaction mixture is cooled, filtered anddistilled under high vacuum. The results according to this procedureindicate that no isomerization or racemization has occurred.

The procedure of converting the enantiomeric carbinols to the chloridesor bromides using thionyl chloride or bromide has the advantage that theenantiomeric R- or S-halides do not need to be distilled for producingthe magnesium-organic compound (IV) (FIG. 2), and the later step ofcarbonation for producing the S- or R-enantiomeric 2-propionic acids(FIGS. 2, 4).

For example, by use of the optically active(+)-1-bromo-1-methyl-2,2-diphenylcyclopropane, an optically activeGrignard reagent (H. M. Walborsky and A. E. Young, J. Amer. Chem. Soc.,83, 2595 (1961)), and an active organolithium compound (H. M. Walborskyand F. J. Impastato, J. Amer. Chem. Soc., 81, 5835 (1959)), have beenprepared. Significantly, the organolithium compound can be carbonatedwith 100% retention of optical activity and configuration.

Normally, the scientific data for formation of Grignard compounds areconsistent with the "D-model" especially for primary alkyl halidesresulting in part of freely diffusing in solution at all times (Garst etal., J. Amer. Chem. Soc., 1985, 108, 2490), hence racemization and lowenantiomeric excess are obtained. However, this conclusion cannot beextrapolated to other substrates.

We have found that the reaction of chiral 2-S-(+)-chloro- orbromo-(4-isobutyl-phenyl)-ethane or the corresponding 2-R-(-) enantiomer(FIG. 1 and FIG. 2) reacts almost quantitatively with magnesium inethereal or THF-solutions at temperatures between 4°-15° C. by keepingthe S- or R-configuration without any significant racemization. The samereactions can be carried out in aprotic solvents also, yielding the sameresults with respect to chemical yields and optical purity by keepingretention of configuration. For carrying out the chemical synthesis, itis not necessary to isolate the S-(+)- or R(-)- Grignard compounds ofthe corresponding chiral-2-substituted ethane in order to achieve thechiral-2-aryl-alkanoic acids. The enantiomeric 2-alkyl-alkanoic acids,especially those of the 2-alkyl-propionic acids, are readily obtained bypassing carbon dioxide through the solution containing the Grignardcompounds. It has been found that the yields of Grignard compounds, andthe subsequent treatment with CO₂, is almost quantitative, and as a rulethe optical purities increase with increasing s-character of the orbitalinvolved, which is further substantiated by forming the correspondingmercuric-II-compounds with high optical purity and retention ofconfiguration (FIG. 2). In the case of the stable mercury-carbon bond,the situation can be explained easily by promoting one of the 6s-electrons to a vacant 6 p-orbital (4f¹⁴ 5d¹⁰ 6s² →4f¹⁴ d¹⁰ 6s¹ 6p¹)yielding two half-filled orbitals which are not equivalent. For energyreasons the bond formed from the 6 p-orbital is more stable than the oneformed by the 6 s-orbital above because a larger overlap is possiblewith the 6 p-orbital. A very stable situation is achieved by the mercurycompounds of the corresponding R- or S-enantiomers of the halides (FIG.2) when in the course of bond formation the 6 s- and the 6 p-orbitalscombine to form new orbitals (two-sp-orbitals) which are equivalent.

To obtain good chemical yields by retaining configuration in the case offorming the Grignard compounds (FIG. 2, IV) and subsequently convertingthe magnesium organic chiral compounds to the corresponding carboxylicacids, it is necessary to have clean and very reactive surfaces ofmagnesium since the adsorbed radicals on the surface of the magnesium(δ-radicals) are retained at the surfaces largely, and they do notdimerize according to our invention, if CO₂ is present on the activeexternal surface also. So no dimerization or dispropartionation doesoccur in ethereal, THF or aprotic solvents, e.g. hexane, benzene,toluene, since the radical is not produced in solution, however,stabilized at the surface of the magnesium metal.

Another way of metallation by retaining configuration with good chemicalyields of the corresponding R- and S-enantiomers and subsequentcarbonation yielding high optically pure 2-aryl-propionic acids of R-and S-enantiomers can be achieved by reaction with methyl-lithium orn-butyllithium (CH₃ Li, R-Li) (FIG. 2), also.

The stereoselective insertion of CO₂ is of utmost importance forproducing metal organic compounds of high optical purities of thecorresponding enantiomer with magnesium and/or methyl lithium as well asfor the mercuric compounds R¹ -HgX₁ with X=Br, C1, CH₃ COO.

It does not necessarily imply that these stereospecific compounds,although new and not being obtained in this high optical purity atpresent, have to be isolated and subsequently treated with CO₂. Theformation of the metal-organic compounds according to FIGS. 1 and 2 canbe coupled to the treatment with CO₂ in one stage, so it is notnecessary to isolate the metalorganic compounds.

Another way of using optically high pure enantiomers, R or S, from1-aryl-haloethane, (FIGS. 3 and 5), being produced easily according tothis invention, of 2-aryl-alkanoic acids, especially 2-aryl-propionicacids, is the direct conversion of the 1-aryl-halides with sodiumtetracarbonyl-ferrate(-II) (Na₂ Fe(CO)₄) in the presence oftriphenylphosphine (Ph₃ P) and subsequent oxidation with iodine--H₂ O tothe corresponding acid, or in the presence of a secondary amine to yieldthe optically pure amide (FIG. 5). The reagent Na₂ Fe(CO)₄ can beprepared by treatment of Fe(CO)₅ with sodium amalgam (NaHg) in THF.

Another method for the conversion of the enantiomeric pure1-aryl-haloethane (FIG. 2) to the acid derivatives makes use of Na₂Fe(CO)₄ also. However, in the presence of CO (FIG. 6), and treatment ofthe intermediate (IV) with oxygen or sodium hypochlorite and subsequenthydrolysis produces the corresponding enantiomeric acid with highoptical purity and chemical yields of 75-80% (see FIG. 6).

The application of the complex between sodiumtetra-cyano-ferrate (II)and phosphine (Ph₃ P) or carbon monoxide, respectively, is usefulespecially in the synthesis of 2-alkyl-alkanoic acids, because of itshigh nucleophilicity and the ease of the integrating inversion reactionof this system. So the halides obtained according to this invention, andthe tosylates react with Na₂ Fe(CO)₄ with typical S_(N) -2 kinetics,stereochemistry (inversion) in order to produce coordinated saturatedanionic d⁸ alkyl iron (0) complexes. According to FIGS. 6 and 7, thisprocedure provides routes from alkyl and acid halides to alkanes,aldehydes, ketones and stereospecific carboxylic acids, including theirderivatives.

A similar method makes use of the conversion of the halides (FIG. 2, IV)to the esters by treatment of the enantiomeric halide (R or S) withnickel carbonyl (Ni(CO)₄) in the presence of an alcohol, preferably1-butanol, and its conjugate base, according to the reaction: ##STR4##

The best chemical yields are obtained for Hal=Br, whereas Hal=C1 and Igive lower yields (˜65%). However, all halides result in high opticalpurities (>95%).

Once having established a stereoselective method of reducing the ketoneto the corresponding enantiomeric alcohol with high optical purity(>97%) and very high chemical yields (>90%), it is possible to produceeither directly from the R-alcohol the S-carboxylic acids or via theR-form of the halide (FIGS. 2, 8 and 9) the corresponding nitrile in thepresence of NaCN and DMSO at 40°-50° C.

Subsequently the enantiomeric S-nitriles can be hydrolyzed to giveeither amides or the corresponding acids. When the S-acid is desired,the reagent of choice is aqueous NaOH containing about 6-8% H₂ O₂,though acid-catalyzed hydrolysis can also be carried out successfully.The chemical yields can be improved by using a strong polar aproticcomplexing solvent such as HMPT for the synthesis of 2-aryl- propionicacids, or by complexing the cyanide ion as a quaternary ammonium salt.This process has the advantage that the condensation can easily bemonitored in a continuous process e.g. as Et₄ ⁺ CN⁻, or C₆ H₅.CH₂ (Me)₃N⁺ CN, applying phase transfer catalysis, or by using crystals such asdicyclohexano-18-crown-6.

The production of the S-enantiomeric nitriles by Et₄ N⁺ CN or Na(K)CNcan be performed according to known methods as described by, e.g. J. M.Teulon et al., J. Med. Chem. 21 (9) 901, (1978), N. Tokutake, Chem.Abstracts 88, 50512f; S. Kothicki et al., Chem. Abstracts 90, 1036526;H. Kobler et al., Liebig's Ann. Chem. 1946, (1978); T. Amano et al.,Chem. Abstracts, 13, 2611 p; Nissan Chemical Industries, Ltd, Chem.Abstracts, 101 90603e, (1984), Nissan Chemical Industries, Ltd., Chem.Abstracts, 101, 6855 h; J. A. Foulkes and J. Hutton, Synth. Commun. 9(7), 625 (1979). However, these procedures mentioned lead to racemates,only.

Usually, the 2-aryl-alkanoic acids especially those of the2-aryl-propionic acids, are scarcely soluble in water; therefore at theend of the reactions the optically active 2-aryl-propionic acids caneasily be isolated by filtration, etc. However, avoiding filtration,crystallizations from organic solvents etc., a suitable method forfurther purification is distillation at high vacuum (˜0.06 mm Hg) due tothe low melting and boiling points of the corresponding enantiomers ofthe 2-aryl-propionic acids. Furthermore, a pharmaceutical product aspure as required by U.S. Pharmacopeia is obtained by acid-base treatmentof the product isolated by filtration, precipitation or distillation inhigh vacuum.

The main advantages of the present stereospecific synthesis of2-aryl-propionic acids from an industrial point of view are as follows:

i) the process is enantio-selective and provides 2-aryl-propionic acidsin high chemical yields and with an enantiomeric ratio higher than theepimeric ratio of known synthetic methods;

ii) the reaction solvents are of economically low cost and have safetyadvantages;

iii) the chiral complexes can be re-used and act at high enantiomericexcess for either enantiomers, R- or S-; so reducing the costs for newchiral complexes;

iv) no further complexes are needed, since the reactions do occur eitherby retaining configuration, or in case of the production of theoptically active nitriles are formed in high chemical yields and highoptical purity with no racemization;

v) the auxiliary substances are economical and of low cost;

vi) the different chemical steps can be performed or reduced to tworeactors, since the intermediates do not need to be isolated;

vii) the optically active 2-aryl-propionic acids (S or R) can beseparated from the reaction mixture by simple filtration, precipitationor distillation in high vacuum;

viii) no high energy costs for carrying out the synthesis on aindustrial scale are involved.

A suitable compound formed by the 2-aryl-propionic acid preferably inthe S-form for pharmaceutical use is the complex between1-amino-1-deoxy-D-glucitol (D-glucamine) and the S-(+) 2-aryl-propionicacids. These compounds have the advantages of being water-soluble, theyare more lipophilic when used as or in transdermal delivery systems anddo reveal antimicrobial activities in vivo and in vitro due to theirsurface activity and form mixed micelles with phospholipids.

It has been found, for example, that 1-amino-1-deoxy-D-glucitol forms,e.g. with R-(-)-ibuprofen a 1:1 complex that is hydrogen bonded (FIG.10). The crystal has cell dimensions of a=8.275 Å, b=40.872 Å, andc=6.420 Å, with four molecules in the unit cell, having the space groupP 2₁ 2₁ 2₂ (#19). The complex structure of the 1:1-complex reveals astrong bond between the hydrogen of the carboxo group of the S-ibuprofenand the O₃ -oxygen of the 1-amino-1-deoxy-D-glucitol with no involvementof the hydrogen of the 1-amino- group (FIG. 10), similar to the S-(+)-ibuprofen-D-glucamine complex.

The (R, S)-ibuprofen forms a 1:1-complex also, showing both enantiomeric(S)-(+)ibuprofen-D-glucamine structure as well as the correspondingR-(-)-ibuprofen-D-glucamine structure (FIG. 11).

Having established the stoichiometric complexes between S-(+)-ibuprofenand D-glucamine or D-ribamine, it is possible to prepare apharmaceutical formulation on the same chemical basis, e.g., interactionbetween the carboxylic acids and the hydroxyl of the D-glucamine, in amelt. The resin of such melt is, e.g., polyoxyethylene glycolates,polyoxyethylene units in general having an average molecular weight of400 to 6000, at most. Polyoxypropylene oxides are very useful, also,since they are able to provide acceptors for hydrogens delivered fromthe carboxylic acids due to deprotonation, forming very stable hydrogenbonding between the 2-aryl-alkanoic acids and this matrix. There areseveral advantages of such a pharmaceutical formulation overmicrocrystals of the pure drug, e.g., S-(+)-ibuprofen, dissolutionproperties, filling in hard capsules due to easy handling, andimportantly the S-(+)-ibuprofen, naproxen and other 2-aryl-propionicacids of the enantiomeric pure state do behave physically the same inthe melt as well as in aqueous solutions yielding a semidilute molecularsolution of, e.g., S-(+)-ibuprofen within the melt. This unexpectedbehavior in the melt as well as in aqueous solution which is provided byscattering experiments and will be described in conjunction with anexample, provides stability of S-(+)-ibuprofen and retention of chiralconfiguration without any racemization which occurs, e.g., on puttingpressure on R-(-)-ibuprofen tablets, or microcrystals due to changing ofthe molal volume of the R-enantiomeric form. This can happen toS-(+)-ibuprofen microcrystals upon pressure also, so it is desirable tohave a solid pharmaceutical formulation which inter alia avoids thesedisadvantages. Furthermore, the resin built up of polyoxyethylenoxideunits having a chain length corresponding to molecular weights between400-6000 normally have melting points of about 50°-55° C., can dissolvecompletely S-(+)-ibuprofen as a molecular solution in the melt. The drugbehaves in this melt as a molecular solution of a solute (drug, e.g.S-(+)-ibuprofen, S-(+)naproxen) in a solvent (polyoxyethylenoxide)according to the laws of solution chemistry in a physical sense. Thisimplies that there is no segregation of S-(+)-ibuprofen from this melt,unless the solid solution is oversaturated by the drug. These isotropicsolutions of S-(+)-ibuprofen in polyoxyethylenoxide (solvent) in themelt as well as diluted in the aqueous media can be followed bysmall-angle X-ray and neutron scattering, and can be compared to thesolid state of the melt also (FIGS. 12 and 13).

Especially, chiral compounds applied as medicinal drugs in certainpharmaceutical formulations can cause difficulties, e.g. racemization,changing in a different polymorphic physical form, deterioration of theenantiomeric, active drug, as well as undesired side effects with regardto in vivo and in vitro dissolution. In order to improve stability,retention of configuration upon pharmaceutical formulation with respectof pure enantiomeric 2-aryl-alkanoic acids, e.g. S-(+)-ibuprofen, S-(+)naproxen, including suitable dissolution rates in vitro and in vivo, ithas been discovered that these achievements can be accomplished bydissolving enantiomeric pure 2-aryl-propionic acids in a melt,consisting of polyoxyethylene glycol, poloxyethylenoxide or mixtures ofthese having weight average molecular weights between 300 to 6000. Inaddition, these resins are mostly water soluble when coming into contactwith watery solutions e.g. emulsions, suspensions includingmicroemulsions and in matrixes with oil in combination with wax or pastewhich are normally used for fillings in soft gelatin capsules. These,and other non-aqueous solutions, emulsions, etc. of pharmaceuticalinterest are described by Schick et al., "Emulsions and EmulsionsTechnology," Vol. 6, Surfactant Science Series, II, Chapter 13,"Cosmetic Emulsions," 1974, 729-730, ed. J. Tissaut--Marcel Dekker Inc.,N.Y., U.S., M. J. Schick in "Nonionic Surfactants," Physical Chemistry,1988, Marcel Dekker, Inc. N.Y., and Basel. The EP-No.: 83109839.4"Anhydrous Emulsion and the Size Thereof" teaches the preparation of apharmaceutical preparation which melts at 37° C., however, on thephysical chemical basis of a emulsion. However, they do have thedisadvantage of leaking when filling hard gelatin capsules due tothixotropic processes.

This newly described process for a melt in a suitable matrix containingcertain amounts of enantiomeric 2-aryl-alkanoic acids or2-aryl-propionic acid has the advantages of being i) a real solution inthe physical sense; ii) a very reliable dosage form of high homogeneityas one finds in real physical solutions; iii) easy to handle technicallywhen using hard gelatin capsules; iv) resistant to demixing - phenomenaon a molecular basis; v) capable of yielding favorite in vitro and invivo dissolution and vi) capable of rapid resorption of the drug.

The surface activity of the enantiomeric 2-aryl-propionic acids arebound only to the S-form. This particular activity can be enhanced bycomplexation with D-glucamine as stated above or with D-ribamine, aswell as by cationic detergents, especially by n-hexadecylpyridinium orbenzethonium cations through binding at the carboxo-groups of theS-2-aryl-propionic acids. The enhancement of the surface activity andtherefore the antimicrobial activity is related to the hydrophobic chainof the hexadecylpyridinium or benzethonium residues due to their lowcritical micelle concentrations (CMC) of approximately 1.5×10⁻⁵ Mol/1when complexed with, e.g. S-(+)-ibuprofen. An advantage of thispharmaceutical formulation is a dosage reduction due to fasterpenetration of the S-(+)-ibuprofen through membranes, skin and reachingthe target cells faster due to micellisation and targeting of theS-(+)-ibuprofen. Therefore, from a medicinal point of view the use ofthe complexes between 2-(S)-aryl-propionic acids or alkanoic acids withcationic detergents, D-glucamine or D-ribamine reduces the dosage of thenon sterodial substances brought about by the vehicle function of thecationic surfactants or D-sugar-alcohols, superior than using simplyalkali or earth alkali metals as well as (S, R)-lysin salts of2-aryl-alkanoic acids.

X-ray diffraction patterns as well as small-angle X-ray scatteringprofiles (FIGS. 11, 12) reveal unstructured behavior in a sense ofdiffuse scattering. Therefore, it is possible to treat the scatteringdata at high and low scattering angles in a thermodynamic way inaddition to the overall electron distribution of the polyoxyetheylenechain (matrix) and solubilized drug, e.g. S-(+)- or R-(-)ibuprofen. Ithas been discovered that the scattering curves of the melt (ligand)containing the matrix and the drug (S-(+)-ibuprofen) dissolved in themelt, have the same scattering profile when the solid melt is dissolvedin aqueous media. Importantly, it has been discovered that a certaindegree of clustering of S-(+)-ibuprofen or S-(+)-naproxen molecules hastaken place in the liquid melt as well as in the solid melt, partlyalong the hydrophilic linear macromolecules such as PEG 1500 orpolyethyleneoxides. It has been found that in the liquid melt theweight-average molecular weight, MW_(app) is of the order25,000+/-5,000, similar for the solid melt and the one in aqueoussolution in the presence of S-(+)-ibuprofen. The weight-average radiusof gyration, Rg, is determined to be of the order Rg=45.0=/-5.0 Å,equivalent of a zig-zac or meander conformation of the linear linked--CH₂ or --OCH₂ -units. Upon addition of S-(+)-ibuprofen or anotherenantiomeric 2-aryl-alkanoic acid MW_(app) is a function of theconcentration of the enantiomeric drug which can be described throughchanges of the second virial coefficient and the isothermalcompressibility coefficient of a one-component solution. The decrease onthe value of the second virial coefficient observed for S-(+) or R-(-)ibuprofen is related to an increase of the included volume of theenantiomeric form within the melt. The molecular explanation for thisunexpected solution behavior in the melt (solid, liquid) and in aqueoussolution is the binding of exposed hydrophobic regions of enantiomeric2-aryl-propionic acids, e.g. isobutylbenzene or naphthylgroups, to CH₂-groups. The free energyΔG of this particular binding of theenantiomeric drugs of the 2-aryl-propionic acids is of the order of0.5-0.7 k_(B).T per PEG molecule, for S-(+)-ibuprofen a value of 0.56k_(B).T/PEG or 0.50 k_(B).T polyoxyethylene unit has been determined.Similar values, although different as found for the S-enantiomers, werediscovered for R-(-)-ibuprofen of 0.45-0.51 k_(B).T per PEG molecule or0.46 k_(B).T per --CH₂ O-unit. The racemate has a ΔG-value of 2.5k_(B).T/PEG, very different from the pure enantiomers. A very likelygeometric description of this melt as well as where dissolved in aqueoussolution is that of a necklace chain. The random coils of the PEO- orPEG-units are wrapped around the hydrophobic cores of theS-(+)-ibuprofen or naproxen molecules whereas the hydrophilic carboxylicacid is located close to oxyethylene (--CH₂ -O)-units or (CH₂)O-units ofthe PEG. The protons of the 2-aryl-propionic acids stereoisomers areswitching between the ethereal or hydroxo-groups of the PEO and PEGmolecules, respectively, and the carboxo groups, as can be shown byFT-IR-investigations also. This situation is also met when going intoaqueous solutions, supported by the interaction of water molecules withthe PEO and PEG residues, protecting the 2-aryl-propionic acidsteroisomers against pH, undesired protonation, racemization at alkalinepH, and keeping retention of configuration. The scattering curves (FIGS.12 and 13) of the solid melts, e.g. PEG or PEO with the solubilizedS-(+)-ibuprofen do not show any interparticle interference effects, evenwhen performing the experiments in aqueous solutions. It has beendiscovered that these particular melts, containing S-(+)-ibuprofen donot show any demixing phenomena when liquid, with increasing temperatureas does PEG and PEO in aqueous solution. Interestingly, this is alsofound in aqueous solutions also, when the melts (solid) go into solutionbetween 37°-40° C.; normally mixtures of this kind do separate withincreasing temperature (phase-separation), depending on the componentsof the mixture when reaching the phase-separation temperature. This isnot the case as observed in this invention, since the repulsive forcesdue to the addition of the enantiomeric 2-aryl-propionic acids are beingreduced in the melts as well as in aqueous solutions. This is alsomanifested through the recording of the scattering curves at highscattering vectors of the melts (FIGS. 14, 15).

The following examples are given further for purely illustrativepurposes of this invention without in any way limiting the same.

All synthetic procedures for obtaining the enantiomeric 2-carbinols haveto be carried out in the absence of moisture, preferably under nitrogenatmosphere.

The (+)-(2S,3R)-4-dimethylamino-3-methyl 1,2-diphenyl-2-butanol (R*OH)should have an [α]_(D) ²⁷ +8.00° (c 9.52, EtOH), mp 56° C., and storedin an desiccator over P₄ O₁₀ in the presence of N₂. This alcohol can berecovered from the hydrochloride and can be repeatedly reused. Thesolvents, ether (Et₂ O), THF, 1,2-dimethoxy-ethane and benzene aredistilled over LiAlH₄ and should be stored over molecular sieves. Thestock solutions of LiAlH₄ should be stored under N₂, and passed througha glass filter (1G2) under N₂ before use.

EXAMPLE 1 Preparation Of R-(+)-2-(4-Isobutyl-Phenyl-)Hydroxyethane

10 g of R*OH are dissolved in 10 ml Et₂ O at 0° C., and 10 ml of a 1Msolution of LiAlH₄ are added to the ethereal solution of R*OH at 0° C.,under continuous stirring; a white pasty precipitate develops at 0° C.It is important that this precipitate be well stirred, so a white,homogeneous suspension can develop. After forming the R*OH.LiAlH₄complex which should be completed within 5 minutes at 0° C., 10 g (5mmol) of 1-(4-[2-methylpropyl]-phenyl) ethanone dissolved in 10 ml ether0° C. are added dropwise to the suspension under continuous mixing bykeeping the temperature between 0° C. to 5° C. constant for one hour.The suspension gives a clear colorless solution after adding the ketonewhich is left for completing the reaction for 12 hours under continuousmixing between 0°-5° C. This mixture is hydrolyzed with 0.5 ml of water,and diluted with hydrochloric acid which is added in order to dissolvethe R*OH for later reuse. Mixing is continued for two hours at 20° C.,until a transparent solution is achieved again.

The clear solution is extracted with Et₂ O, leaving R*OH.HCl in theaqueous phase, and the R-(+)-2-(4-isobutyl)hydroxyethane in the organicphase. The ethereal extracts are combined, concentrated and distilled inhigh vacuum (0.1 mm Hg; b.p. 80° C.) which gives a clear, colorlessfairly viscous liquid (1.15 g, 94% yield), containing no unreducedketone as measured by HPLC-techniques and confirmed by the absence ofthe carbonyl infrared stretching frequency. The optical purity isdetermined by conversion to the MTPA derivative and by measuring theNMR-spectrum gives a value of 98% e.e.

Neutralization of the acid extract yields recovered chiral R*OH with[α]_(D) ²⁰ +8.21° (C 11.0, EtOH).

It is observed that addition of molecular sieves, e.g. as zeolites,increases the kinetics of formation of the enantiomeric R (+)-carbinolat 0° C., from the reduction of the 1-(4-[2-methylpropyl]phenyl)ethanone. 5 g of R*OH are dissolved in 5 ml Et₂ O, or THF, benzene,1,2-dimethoxy ethane, toluene, in the presence of 0.2 g commerciallyactive 4A molecular sieves, and heavily stirred under a stream of N₂. Tothis mixture a solution of 5 ml of a 1M solution of LiAlH₄ is added at0° C., under continuous mixing. The reaction time for converting theunsymmetrical ketone to the corresponding enantiomeric R-carbinol can bereduced to two hours or less. For technical reasons the molecular sievescan be centrifuged and reused as well as R*OH as described above.

In another procedure the ketone is added immediately after forming thereagent, R*OH.LiAlH₄, in the presence of the molecular sieves, which hasthe advantage that no unreduced ketone is present in the R-carbinolproduced. This is especially important to achieve almost quantitativechemical yields of unsubstituted R-1-naphthylhydroxyethane, orR-1-[2-fluoro-4-diphenyl]-hydroxyethane,R-1-[4-chloro-2-phenyl]-hydroxyethane,R-1-[6-hydroxy-2-naphtyl]-1-hydroxyethane andR-1-[6-methoxy-2-naphthyl]hydroxyethane.

EXAMPLE 2 Preparation Of S-1-(4-Isobutylphenyl)-Hydroxyethane

10 g of R*OH (35 mmol) are dissolved in 20 ml Et₂ O, and 15.6 mmol ofLiAlH₄, dissolved in 30 ml of Et₂ o are added and stirred at 20° C. inthe presence of 0.2 g molecular sieves. The suspension is refluxed for10 minutes under continuous stirring in the presence of the molecularsieves. The solution which should have clear supernatant in the presenceof the molecular sieves is stored at 20° C. for 20-24 hours in case ofno rapid mixing; however, upon rapid mixing at 20° C. the formation ofthe chiral complex in the presence of molecular sieves is complete aftertwo hours. The reduction is carried out as described above by addingdropwise 10 mmol (2.0 g) of 1-[4-(2-methylpropyl)]phenyl-ethanone andleaving the solution to react for 8 hours. The reaction time withrespect to reduction to the corresponding S-(-)carbinol can be decreasedby rapid mixing in the presence of the molecular sieves without raisingthe temperature above 20° C. The processing of the S-(-)carbinol is thesame as described above.

The optical purity is determined to be 97% as determined by NMR methodsand the chemical yield of pure product is almost 95%.

The reduction of the ketone can be performed in aprotic solvents, also,e.g. benzene, toluene or hexane. In order to have good chemical yieldsof enantiomeric carbinols it is necessary to perform these reactionsunder vigorous stirring in the presence of molecular sieves and glassbeads. The reaction times, modes of addition of the unsymmetricalketones, ratio of R*OH to LiAlH₄ and temperature conditions are the sameas described above.

The reduction described above can be carried out in well stirred,continuous tank reactors because it is particularly suitable for liquidphase reactions in large scale industrial productions. It gives aconsistent product quality (optical purity) ease of automatic controland low man power requirements. Since in a stirred tank reactor thereactants, e.g. R*OH.LiAlH₄ and the ketone, are diluted immediately onentering the tank which favors the desired reaction (constant ratio ofLiAlH₄ R*OH) and supresses the formation of byproducts, volume andtemperature of the tank are readily controlled, so hot spots are lesslikely to occur, especially in the presence of molecular sieves when thecontinuous stirring is well adjusted.

The chemical yields are of the order of 85-98% in the absence ofmoisture and high vacuum distillation of the enantiomeric carbinols.

EXAMPLE 3 Reduction Of The Ketone With (-) 2,2-Dihydroxy-1,1-BinaphthylTo S-(-)-1-(4-Isobutylphenyl)-Hydroxyethane

To a 1.5M THF solution or LiAlH₄ (8.0 mmol) under nitrogen atmosphere inthe presence of molecular sieves (0.2 g 4A zeolites) ethanol in THF (2M,8.50 mmol) are added at 0° C. This solution is continuously stirred whenS-(-)-2,2'-dihydroxy-1,1-binaphthyl reagent (8.5 mmol) THF (0.64 mmol)is added at 0° C. After addition of theS(-)-2,2'-dihydroxy-1,1-binaphthyl reagent at 0° C., the solution isstirred continuously for one hour at 20° C. without having developed awhite precipitate as observed normally. The chiral reagent formed iscooled down to -20° C., and 2.50 mmol of 1-[4-(2-methylpropyl)]phenyl-ethanone, dissolved in THF (1M solution) is added undercontinuous mixing and kept for 8 hours at -20° C. under continuousstirring. The reaction is stopped by adding 1.0N HCl at -20° C., thechiral reagent recovered, and the work-up with ether followed bydistillation afforded optically pureS-(-)-1-(4-isobutylphenyl)-hydroxyethane, 310 mg, 81%, in an opticalyield of almost 95% in enantiomeric excess and configuration. The chiralreagent can be be reused after recrystallization from benzene withoutany noticeable racemization.

EXAMPLE 4 Preparation Of S-(+)-2-[4-Isobutylphenyl] Propionic Acid

10 g of S-(-)-1-[4-isobutylphenyl]-hydroxyethane (56 mmol) are dissolvedin 20 ml 1.4 dioxane at 20° C. in the presence of molecular sieves 4Aunder stirring. 5.0 ml SOCl₂ (=60 mmol), dissolved in 5 ml 1.4-dioxane,is added dropwise under continuous stirring over a period of 10 minutesby keeping the temperature at 20° C. After one hour the reaction iscomplete and the thionyl-chloride is recovered through evaporation bybubbling N₂ through the solution. TheS-(-)-1-[4-isobutylphenyl]-chloroethane does not need to be separatedsince the solution is used immediately for metallation with Mg or Hg(00C CH₃)₂. To this solution containing 11 g ofS-(-)-1-(-)-[4-isobutylphenyl]-chloroethane 1.40 g Mg (0.055M) in thepresence of iodine is added at 0° C., and after a period of 10-30minutes a vigorous reaction starts, so sometimes cooling may benecessary in order to avoid Wurtz synthesis and biradical production.The solution turns from light yellow to light brown at the end of thereaction when carbon dioxide is passed through the reaction at 0°-5° C.,under continuous mixing. The Grignard compound which is derived fromS-(+)-1-[4-isobutylphenyl]chloroethane (or bromoethane when SOBr₂ isused) is diluted by Et₂ O or THF (or benzene, toluene) when passing dryCO₂ through the solution under continuous stirring which is essentialfor obtaining high chemical yield of optically pure S-(+) ibuprofen. Thecontinuous addition CO₂ to the S-Grignard compound and the production ofthe S-carboxylic acid makes it necessary to add dry 1,4 dioxanecontinuously as the S-carboxylic acid develops and saturates thesolvent. After 20 minutes the reaction is complete, is separated fromsolid residues and is transferred to high vacuum distillation. Thesolution is concentrated and distilled at 2 mmHg (0.06-2 mm Hg) at120°-98° C., to give 9.30 g (80%) of S-(+) ibuprofen: NMR (CDCl₃) S 0.91(d,J=7H, 6H), 1.50 (d,J=8 Hz, 3H), 1.84 (nonet,1H),2.96 (brd,27H7,2H),3.72(g, 1H),7.01-7.32 (AA'BB',4H), 9.78 (br. sl H). [α]_(D) ²⁵+58° (95%, EtOH).

EXAMPLE 5 Preparation Of R-(-)-2-[Isobutylphenyl]-Propionic Acid

The same procedure can be performed as outlined in Example 3. However,the R-(+)-1-[4-isobutylphenyl]-chloroethane can be easily produced fromS-(-)-1-[4-isobutylphenyl]-hydroxyethane by reacting SOCl₂ in pyridinein the presence of water. 10 g ofS-(-)-1-[4-isobutylphenyl]-hydroxyethane (56 mmol) is dissolved in 15 gpyridine, containing 10% (w/w) water at 20° C. Under continuous mixing6.7 g SOCl₂ (equivalent to 4.1 ml) is added and refluxed for 20 minutes.After removing the excess of SOCl₂ and pyridine (b.p. 116° C., 760 mmHg)the chloride is distilled at 6 mmHg (bp 98.3° C.) to give 9.59 g ofR-(+)-1-[4-isobutylphenyl]chloroethane (86.6%): NMR (C Cl₄) δ0.90 (d,J,7Hz,6H), 1.84 (d,J7 Hz,3H), 1.86 (nonet, 1H), 2.48 (d,J= 7 Hz,2H), 5.15(q, 1H),7.10-7.44 (AA'BB'4H). Analysis: calc. for C₁₂ H₁₇ jCl:C73,26;H,8.7 , Cl, 18.01, found: (73,40% H: 8.79% Cl 18.09% [α]_(D) ²⁵-29.5° (C 1.9%, (CCl₄);

The corresponding Grignard reagent (0.9M-1.5M) in Et₂ O is prepared inapproximately 80% yield by adding slowly a solution of the halide in Et₂O to magnesium at 4° C. as described above in Example 3. The procedurefor carbonation or mecuration in the presence of H_(g) (OOCCH₃)₂, [Hg(CN)₂ ]₂ or HgCl₂ is similarly as described in Example 4. The chemicalyield of R-(-) ibuprofen is 78% and the optical purity almost 98%.

EXAMPLE 6 Synthesis Of S-(+) Ibuprofen Via Nitrile And SubsequentHydrolysis

10 g R-(+)-1-[4-isobutylphenyl)-chloroethane (50.5 mmol) are dissolvedin 25 ml EtOH and 15 ml water, and reacted with 2.95 g (60 mmol) sodiumcyanide dissolved in 10 ml water under dropwise addition of the cyanidesolution under continuous stirring. The mixture is refluxed for one hourand allowed to cool down to 20° C. The precipitated sodium chloride isfiltered off and the supernatant, containing water and EtOH are driedand EtOH is distilled from the remaining liquid, which contains theS-(+)-1-[4-isobutyl phenyl]-ethyl cyanide. (Chemical yield 88%). ThisS-(+) cyanide is dissolved in 15 ml EtOH and 30 ml water, which contains9 g (0.45 mol) sodium hydroxide and 10% (w/w) H₂ O₂ and heated underreflux conditions for one hour. After cooling to room temperature thereaction mixture is diluted with 100 ml water until a clear andtransparent solution appears. This solution is cooled down to 0° C. and100 ml of diluted hydrochloric acid is subsequently added, whenS-(+)-ibuprofen precipitates as small crystals. The S-(+)-ibuprofencrystals are collected, washed with dilute hydrochloric acid and driedover Ca Cl₂. The chemical yield is 94% and the melting point was 51°-54°C. [α]_(D) ²⁰ +60° (95% EtOH).

EXAMPLE 7 Synthesis Of S-(+)-Ibuprofen From TheR-(+)-1-[4-IsobutylPhenyl]-Chloroethane With Sodium TetraCarbonyl-Ferrate And Carbon Monoxide

10 ml R-(+)-1-[4-isobutylphenyl]-chloroethane (50.5 mmol) are dissolvedin 150 ml of dimethyl formamide (DMF) (0.033M) under rapid mixing and N₂-stream, 10.8 g sodium-tetracarbonyl-ferrate-II which is freshlyprepared by treatment of iron-pentacarbonyl Fe(CO)₅ with sodium amalgamand THF at 20° C., are added by continuous mixing. The solution iscooled down to 10° C. and a stream of carbon monoxide is passed throughthe solution. Normally, the reaction is finished after 1-2 hours,depending on temperature and solvents (THF, DMF,DMSO); however, it caneasily be monitored when an excess of carbon monoxide is leaving thesolution in the presence of N₂. The oxidative cleavage to thecorresponding S-(+)-2-[isobutyl phenyl] propionic acid is achieved byadding an aqueous solution of sodium hypochloride with subsequentaddition of 0.1M hydrochloric acid by keeping the reaction temperatureat 10° C. Care must be taken to add enough hydrochloric acid since mostof the protons are used for precipitation of S-(+)-ibuprofen in aqueoussolution for recovery of the free acid.

The corresponding amide from S-(+)-ibuprofen can be prepared by usingtriphenyl phosphine (Ph₃ P) instead of carbon monoxide in the presenceof sodium tetracarbonyl ferrate (II)(Na₂ Fe(CO₄)). 10 g ofR-(+)-1-[4-isobutyl phenyl]-chlorethane are dispered in 30 ml benzene inthe presence of 10.8 g sodium tetracarbonyl ferrate-(II) at 20° C. 13.4g triphenyl phosphine (0.051 mol) dissolved in dry benzene are addeddropwise during a period of time of 20 minutes under N₂ atmosphere. Themixture is refluxed under continuous stirring for three hours, thereaction mixture is left standing for one hour at 20° C. with subsequentquenching of the reaction with methyl-benzylamide. The small crystals ofS-(+)-ibuprofen methyl benzylamide are filtered off, recrystallized fromTHF/DMF, and analyzed by HPLC-methods for optical purity: theHPLC-analysis shows the presence of 98% diastereisomer corresponding toS-2-(4-isobutyl phenyl) propionic acid at retention times of 2.79minutes and 2% diastereisomer corresponding to R-2-(4-isobutyl phenyl)propionic acid at retention times of 2.38 minutes. The chemical yieldsfor producing the S-2-carboxylic acid from the correspondingR-(+)-1-[4-isobutyl phenyl]-chloroethane are, in the presence of carbonmonoxide, almost 95% with an optical purity of 95-98%, and 90% in thepresence of triphenyl phosphine, respectively.

EXAMPLE 8 Preparation Of Complexes Between S-(+)-Ibuprofen And1-Amino-1-Deoxy-D-Glucitol

206.27 (250.0) mg S-(+)-ibuprofen and 236.72 (181.19) mg of1-amino-1-deoxy-D-glucitol are dissolved in 6 ml of water, subsequentlytreated at 45° C., and sonified for one hour. The clear solution can bestored and used for medical practice after sterilization. The complexcan be crystallized from ethereal or alcoholic solution by adding thesesolvents at 20° C., under continuous stirring to an aqueous solution ofS-(+)-ibuprofen and 1-amino-1-deoxy-D-glucitol (pH 7.5). themicrocrystalline precipitate can be collected by filtration withsubsequent drying over CaCl₂ under N₂ -atmosphere. In addition, if nocrystalline precipitate can be certified, the supernatant is discardedand the precipitate is dried over P₂ O₅ /CaCl₂ in vacuo at 30° C. Themelting point of the amorphous complex is 61° C.; of the crystallinespecimen is 106.5° C. By applying other precipitating solvents, e.g.acetone or alkyl-aryl ketones, DMF or petrol ether different crystallineforms are observed revealing a certain degree of polymorphism of theseparticular sugar-S-(+)-ibuprofen complexes.

EXAMPLE 9 Synthesis Of S-(+)-2-(6-Methoxy-2-Naphthyl)-Propionic Acid

Very good chemical yields (80%) of this compound are obtained in highoptical purity (95%) according to the routes outlined in Examples 4 and5, especially when using Collman's reagent in the presence of carbonmonoxide with subsequent hypochlorite oxidation.

Recrystallization of the raw material with mp 252-253 ° C. yieldscrystalline specimens having a melting point of 154° C. (lit mp 152-154°C.); [α]_(D) ²⁵ +64.5° (C=1.08 CHCl₃), NMR (CHCl₃); 1.6 (D, 3H,CH--CH₃); 3.92 (S, 3H, OCH₃), 3.88 (g, 1H, CH) and 7-7.9 (m, 6H,aromatic).

MS resulted in the following spectra (FAB, glycerol matrix): m/z=23,[M+H]³⁰, 185 [M-HCOOH+H]³⁰, 323 [M+6+H]³⁰ , 115 [6+Na]⁺ and 229 [m-H ⁻with 6=glycerol.

Measurements of the optical purity of this compound are accomplished byconverting the carboxylic acid to the corresponding amide usingS-(-)-methylbenzyl amine as described above, using HPLC-techniques whichgive the following results:

the chromatographic composition of the formed diastereoisomers are 3.6%R-2-(6-methoxy-2-naphthyl)-propionamide (6.15 min) and 96.4%S-2-(6-methoxy-2-naphthyl)-propionamide (6.95 min).

EXAMPLE 10 Synthesis Of S-(+)-2-(5-Bromo-6-Methoxy-2-Naphthyl)-PropionicAcid, As Methyl Ester

After stereospecific reduction of the ketone as described in Examples 1and 2 with (+)-(2S,3R)-4-dimethylamino-3-methyl-1-2-diphenyl 2 butanoland LiAlH₄ to the corresponding R-carbinol, subsequently converted tothe R-halide and treatment with sodium tetracarbonyl ferrate-II in thepresence of triphenylphosphine yields the corresponding carboxylic acidin a chemical yield of 75% having an optical purity of almost 95%. Themelting point, mp, is determined to be 168° C.; [α]_(D) ²⁰ +42.7 (0.8%)in chloroform. The methyl ester is easily obtained by reacting thecarboxylic acid with diazo-methane, following evaporation of the solventunder reduced pressure, which gives the optically pureS-(+)-2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid methylester.

Melting point, mp 96° C.; [α]_(D) ²⁰ +52.5 (c=0.5, CHCl₃). The productis considered to be optically pure by ^(l) H-MMR (200 MHz) analysis,which is carried out in CHCl₃ applying an optically active shiftingagent as described above (EuIII-trix [3-heptafluoropropylhydroxymethylene)-d-camphorate].

EXAMPLE 11 Synthesis of R-(-)-2-(5-Bromo-6-Methoxy-2-Naphthyl)-PropionicAcid

Performing the reduction of the ketone with (-) 2,2dihydroxy-1,1'-binaphthyl-LiAlH₄ -ROH complex, as described in Example 2in the presence of molecular sieves, yields an optically pureS-2-(5-bromo-6-methoxy-2-naphthyl)-hydroxy ethane (98%) in almostquantitative chemical yield. Following the route via nitrile withfollowing oxidation to the corresponding carboxylic acid yields inalmost 75% chemical yields of the optically pureR-(-)-2-(5-bromo-6-methoxy-2-naphthyl) propionic acid, having a meltingpoint=168° C.; [α]_(D) ²⁰ -42.0 (c=0.6%, chloroform).

EXAMPLE 12 Synthesis of 2-S-(+)-(4-Chlorphenyl)-3-Methyl-Butanoic AcidFrom 1-(4-Chlorphenyl)-3-Methylbutanone

The ketone can be prepared from 3-methyl-butyryl chloride (128.6 g=1.07moles) through Friedel-Craftsreaction with aluminium chloride (153.7g=1.15 moles) in methylene chloride under the continuous addition ofchlorbenzene (100 g=0.80 moles). The stereospecific reduction of thisketone with (+)-(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanolin the presence of LiAlH₄ is performed at 20° C. as described inExample 1. The R-carbinol which is 90% pure with respect to opticalpurity is converted to the corresponding R-halide with SOCl₂ andpyridine, subsequently treated with sodiumtetracarbonyl-ferrate-II inthe presence of carbon monoxide as described in Example 5.

The obtained crude carboxylic acid is purified on DEAF-Sephadex-A50,applying a linear gradient at pH 7.9, ranging from 0.001M K₂ HPO₄ to0.01M K₂ HPO₄ in a total volume of 1000 ml. The fraction containingoptically active materials (+) are pooled, lyophilized and investigatedfor optical purity. The overall chemical yield is 71%, [α]_(D) ²⁰ +39.7(c 0 1%, chloroform).

EXAMPLE 13

The corresponding biphenyl and phenoxy-propionic acid derivatives can beprepared following the same procedures as outlined in the Examples 1-5.Below are listed some compounds which are prepared in accordance withthe routes of Example 1-5, showing the optical activity and chemicalyields.

S-(+)-2-(2-fluoro-4-biphenyl) propionic acid, [α]_(D) ²⁰ +44.7, chemicalyield 80%,

S-(+)-2-(2-[4-(2-fluorophenoxy)phenyl]) propionic acid, having [α]_(D)²⁰ +49, chemical yield 70%, and

S-(+)--2-(2-hydroxy-4-biphenyl)propionic acid, [α]_(D) ²⁰ +47.

EXAMPLE 14 Preparation Of Solid Melts Of S-(+)Ibuprofen AndPolyethylenglycol 1500

500 g of polyethylenglycol 1500 are melted in the absence of water in acontainer at 55° C. ±3° C., under continuous stirring. Solid 500 gS-(+)-ibuprofen is added under continuous stirring, also. It is possibleto mix 500 g of polyethylenglycol 1500 with 500 g S-(+)-ibuprofen andmelt the mixture in a container under stirring at 55° C. A clear, liquidmelt is formed which is transparent when viewed at day light, when theliquid melt is cooled down to 40° C. This liquid (40° C.) can be filledin hard gelatin capsules easily in any dosage form one would like tohave. After the appropiate filling the hard gelatin capsules are left atapproximately 32° C., where a solid is being obtained which does notneed to be sealed.

In order to accommodate fast solidifying of the liquid contents of themixture, one can add some crystalline seeds of either S-(+)-ibuprofen or(R,S)-ibuprofen in order to increase the number of nucleation sites.

What is claimed is:
 1. A process for forming a pharmaceutically activecarboxylic acid in stereospecific form having the formula ##STR5## or apharmaceutically acceptable salt thereof wherein R is lower alkyl andAris a monocyclic, polycyclic or orthocondensed polycyclic aromatic grouphaving up to 12 carbons in the aromatic ring and which may besubstituted or unsubstituted in the aromatic ring which comprises: (a)reacting a carbonyl substrate of the formula: ##STR6## with an effectiveamount of a stereospecific reagent selected from the group consisting of(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol and2,2'-dihydroxy-1,1-binaphthyl in the presence of lithium aluminumhydride and in an organic solvent to form a R or S carbinol of theformula: ##STR7## (b) reacting the product thereof with a halogenatingagent to form the stereospecific R or S halide; (c) reacting the halidewith cyanide to form the corresponding nitrile with inversion; and (d)hydrolyzing the nitrile to form the stereospecific carboxylic acid. 2.The process according to claim 1 wherein the carboxylic acid formed isin the S configuration.
 3. The process according to claim 3 wherein theproduct is ibuprofen or naproxen.
 4. The process according to claim 1wherein the product is S-ibuprofen or S-naproxen.
 5. The process inaccordance with claim 1 wherein the halide is the R-halide.
 6. Theprocess in accordance with claim 5 in which the halide is in the Rconfiguration having the formula ##STR8## wherein Hal is Cl or Br. 7.The process in accordance with claim 1 in which the S-carbinol isreacted with SOCl₂ or SOBr₂ in a solvent consisting of pyridine andwater.
 8. The process according to claim 1 in which the R halide isformed by reacting the R-carbinol with cyanuric chloride, SOCl₂ or SOBr₂in anhydrous solvent, wherein the R halide is in the R configurationhaving the formula ##STR9## wherein Hal is Cl or Br.
 9. The processaccording to claim 8 in which the solvent is pyridine or dioxane. 10.The process according to claim 1 in which the cyanide is alkali cyanide.11. The process according to claim 10 in which the alkali cyanide issodium cyanide or potassium cyanide.
 12. The process according to claim1 wherein the halide is the R-halide and the cyanide is alkali cyanide.13. The process according to claim 1 wherein the product is hydrolyzedwith acid.
 14. The process according to claim 13 in which the product ishydrolyzed with aqueous hydroxide base containing about 6-8% H₂ O₂. 15.The process according to claim 14 in which the base is sodium hydroxide.16. The process according to claim 15 in which the R halide is reactedwith potassium cyanide and the nitrile product thus formed is hydrolyzedwith aqueous NaOH containing about 6-8% H₂ O₂.
 17. The process accordingto claim 15 wherein the R-halide is reacted with sodium cyanide and thenitrile product thus formed is hydrolyzed with aqueous NaOH containingabout 6-8% H₂ O₂.
 18. A process for forming a pharmaceutically activecarboxylic acid in stereospecific form having the formula ##STR10## or apharmaceutically acceptable salt thereof wherein R is lower alkyl andAris a monocyclic, polycyclic or othocondensed polycyclic aromatic grouphaving up to 12 carbons in the aromatic ring and which may besubstituted or unsubstituted in the aromatic ring which comprises: (a)reacting a carbonyl substrate of the formula: ##STR11## with aneffective amount of (S)-(-)-1,1-diphenylprolinol in the presence of acomplex between boron hydride and tetrahydrofuran in an organic solventto form a R or S carbinol of the formula: ##STR12## (b) reacting theproduct thereof with a halogenating agent to form the stereospecific Ror S halide; (c) reacting the halide with cyanide to form thecorresponding nitrile with inversion; and (d) hydrolyzing the nitrile toform the stereospecific carboxylic acid.
 19. The process according toclaim 18 in which R is methyl.
 20. The process according to claim 1 inwhich molecular sieves are additionally present in step (a).
 21. Theprocess according to claim 20 in which the molecular sieves are 3Å or 4Åmolecular sieves.
 22. A process for preparing in the S configuration acompound of the formula: ##STR13## or a pharmaceutically acceptable saltthereof wherein R is lower alkyl andAr is a monocyclic, polycyclic ororthocondensed polycyclic aromatic compound having up to 12 carbons inthe aromatic ring and which may be substituted or unsubstituted in thearomatic ring which comprises (a) reacting a carbonyl substrate of theformula ##STR14## under effective conditions in an organic solvent withan effective amount of a reagent in the presence of lithium aluminumhydride, said reagent consisting of(+)-4-dimethylamino-3-methyl-1,2,diphenyl-2-butanol and2,2'-dihydroxy-1,1-binaphthyl or an effective amount of(S)-(-)-1,1-diphenylprolinol in the presence of a complex between boronhydride and tetrahydrofuran to form a S carbinol of the formula##STR15## (b) reacting the carbinol with an effective amount of ahalogenating agent to form the corresponding R-halide; (c) reacting theR-halide with an effective amount of cyanide to form the S-nitrile; and(d)hydrolyzing the S-nitrile to form the S-carboxylic acid.
 23. Theprocess according to claim 22 wherein the reagent is(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol or2,2-dihydroxy-1,1-binaphthyl.
 24. The process according to claim 23wherein molecular sieves are additionally present.
 25. The processaccording to claim 24 wherein the molecular sieves are 3Å or 4Åmolecular sieves.
 26. The process according to claim 22 in which R ismethyl.
 27. The process according to claim 22 in which Ar is4-isobutylphenyl, 6-methoxy-2-naphthyl, 3-phenoxyphenyl,2'-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl,5-chloro-6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl,4-chlorophenyl, 4-difluoromethoxyphenyl, 6-hydroxy-2-naphthyl or5-bromo-6-hydroxy-2-naphthyl.
 28. The process according to claim 22wherein ##STR16##
 29. The process according to claim 22 wherein thereagent is (+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol and theprocess of step (a) is conducted at about -70° C.
 30. The processaccording to claim 22 wherein Ar is ##STR17## R is methyl, the reagentis (+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol and the reactiontemperature of step (a) is about -70° C.
 31. The process according toclaim 22 wherein the reagent is 2,2'-dihydroxy-1,1-binaphthyl and thetemperature of step (a) is approximately 20° C.
 32. The processaccording to claim 22 wherein Ar is ##STR18## R is methyl, and thereagent is 2,2'-dihydroxy-1,1'-binaphthyl and the temperature of step(a) is approximately 20° C.
 33. The process according to claim 22wherein the R-halide has the formula ##STR19## wherein Hal is chlorideor bromide.
 34. The process according to claim 22 in which the Scarbinol is reacted with SOCl₂ or SOBr₂ in a solvent consisting ofpyridine and water.
 35. The process according to claim 22 in which thecyanide is alkali cyanide.
 36. The process according to claim 33 whereinthe alkali cyanide is sodium cyanide or potassium cyanide.
 37. Theprocess according to claim 22 wherein the S-nitrile is hydrolyzed withacid.
 38. The process according to claim 22 in which the S-nitrile ishydrolyzed with aqueous hydroxide base containing about 6-8% H₂ O₂. 39.The process according to claim 38 in which the base is sodium hydroxide.40. A process for preparing in the R configuration a compound of theformula ##STR20## or a pharmaceutically effective salt thereof wherein Ris lower alkyl;Ar is a monocyclic, polycyclic or orthocondensedpolycyclic aromatic compound having up to 12 carbons in the aromaticring and which may be unsubstituted or substituted in the aromatic ringwhich comprises (a) reacting a carbonyl substrate of the formula:##STR21## at effective temperature with an effective amount of a reagentin the presence of lithium aluminum hydride, said reagent consisting of(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol and2,2'-dihydroxy-1,1-binaphthyl or with an effective amount of(S)-(-)-1,1-diphenylprolinol in the presence of a complex between boronhydride and tetrahydrofuran to form a R carbinol of the formula:##STR22## (b) reacting the carbinol with an effective amount of ahalogenating agent to form the corresponding S-halide, (c) reacting theS-halide with an effective amount of cyanide to form the R-nitrile and(d) hydrolyzing the R-nitrile to form the R-carboxylic acid.
 41. Theprocess according to claim 40 wherein the reagent is(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol or2,2-dihydroxy-1,1-binaphthyl.
 42. The process according to claim 41wherein molecular sieves are additionally present.
 43. The processaccording to claim 42 wherein the molecular sieves are 3Å or 4Åmolecular sieves.
 44. The process according to claim 40 in which R ismethyl.
 45. The process according to claim 40 in which Ar is4-isobutylphenyl, 6-methoxy-2-methoxy-2-naphthyl, 3-phenoxyphenyl,2'-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl,5-chloro-6-methoxy-2-naphthyl, 5-bromo-6-methoxy-2-naphthyl,4-chlorophenyl, 4-difluoromethoxyphenyl, 6-hydroxy-2-naphthyl or5-bromo-6-hydroxy-2-naphthyl.
 46. The process according to claim 40wherein ##STR23##
 47. The process according to claim 40 wherein thetemperature of step (a) is about 0° C. and the reagent is(+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol.
 48. The processaccording to claim 40, wherein Ar is ##STR24## R is methyl, the reagentis (+)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol and the reactiontemperature of step (a) is about 0° C.
 49. The process according toclaim 40 wherein the R-halide has the formula ##STR25## wherein Hal ischloride or bromide.
 50. The process according to claim 40 in which theS carbinol is reacted with SOCl₂ or SOBr₂ in a solvent consisting ofpyridine and water.
 51. The process according to claim 40 in which thecyanide is alkali cyanide.
 52. The process according to claim 51 whereinthe alkali cyanide is sodium cyanide or potassium cyanide.
 53. Theprocess according to claim 40 wherein the R-nitrile is hydrolyzed withacid.
 54. The process according to claim 40 in which the S-cyanide ishydrolyzed with aqueous hydroxide base containing about 6-8% H₂ O₂. 55.The process according to claim 40 in which the base is sodium hydroxide.56. The process according to claim 22 wherein step (a) comprises addingto and dissolving 3-methyl-1,2-diphenyl-2-butanol and LiAlH₄ an organicsolvent, allowing said solution to stand at a temperature of about -70°C. to 0° C. for a time sufficient to form a microemulsion andsubsequently adding said carbonyl substrate thereto.
 57. The processaccording to claim 26 wherein the carbonyl substrate is2-(4-isobutylphenyl)-methyl ketone or 1-[4-2-methylpropyl]phenylethanone.
 58. The process according to claim 40 wherein step (a)comprises adding (+) 4-dimethyl amino-3-methyl-1,2-diphenyl-2-butanoland LiAH₄ to an organic solvent with stirring at temperatures rangingfrom 0° C. to -50° C. and before evolution of hydrogen, adding thecarbonyl substrate thereto.
 59. The process of claim 58 wherein thecarbonyl substrate is added within ten minutes after the addition of thebutanol and LiAH₄ to the organic solution.
 60. The process according toclaim 58 wherein the carbonyl reagent is 2-(4-isobutylphenyl) methylketone or 1-[4-2-methylpropyl]phenyl ethanone.
 61. The process accordingto claim 1 wherein the carbinol formed in step (a) is the S-carbinol.62. The process according to claim 22 in which the R-halide is reactedwith potassium cyanide, and the nitrile product thus formed ishydrolyzed with acid.
 63. The process according to claim 22 wherein theR-halide is reacted with sodium cyanide and the nitrile product thusformed is hydrolyzed with acid.
 64. The process according to claim 1 inwhich the halogenating agent is thionyl bromide, thionyl chloride orcyanuric chloride.
 65. The process according to claim 22 in which thehalogenating agent is SOCl₂, SOBr₂ or cyanuric chloride.
 66. The processaccording to claim 40 in which the halogenating agent is SOCl₄, SOBr₂ orcyanuric chloride.